EP0861246B1 - Prolylendopeptidase-inhibitoren, ihre herstellung und ihre pharmazeutische verwendung - Google Patents

Prolylendopeptidase-inhibitoren, ihre herstellung und ihre pharmazeutische verwendung Download PDF

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EP0861246B1
EP0861246B1 EP96925926A EP96925926A EP0861246B1 EP 0861246 B1 EP0861246 B1 EP 0861246B1 EP 96925926 A EP96925926 A EP 96925926A EP 96925926 A EP96925926 A EP 96925926A EP 0861246 B1 EP0861246 B1 EP 0861246B1
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formula
compounds
carbon atoms
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isomers
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EP0861246A1 (de
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Károly KANAI
Sándor ERDO
Andrea Szappanos
Judit Bence
István HERMECZ
Györgyné SZVOBODA
Sándor BATORI
Gergely Heja
Mária BALOGH
Agnes Horvath
Judit Sipos
Bodor Veronika Bartane
Zsolt Parkany
Viktor Lakics
Péter MOLNAR
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SANDOR, ERDOE DR.
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Sandor Erdo Dr
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    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
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    • C07D277/06—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/08—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing alicyclic rings
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    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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    • C07D473/06—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3

Definitions

  • the present invention relates to new compounds of the general formula (I), to pharmaceutical compositions containing them, and to a process for the preparation of these compounds.
  • the new compounds of the general formula I are useful for the treatment of CNS diseases by inhibition of certain enzymes described later on.
  • Prolyl endopeptidase PE or PEP is a post-proline cleaving enzyme (PPCE). It is widespread in mammalian species and can be found in various organs of the body. The level of the enzyme is the highest in the brain, testes and skeletal muscles (Yoshimoto, T., Ogita, K., Walter, R., Koida, M. and Tsuru, D.: Biochem. Biophys. Acta, 569, (1979), 184-192).
  • PEP has some important roles in the memory process due to the fact that its substrates are biologically active neuropeptides (substance P, thyrotropin-releasing hormone, Arg 8 -vasopressin). These neuropeptides exert characteristic pharmacological effects on the central nervous system: they are capable of changing the performance of animals and humans in learning and memory tasks (Toide, K., Iwamoto Z., Fujiwara, T., and Abe, H.: J. Pharm. Exp. Therapeutics, 274, (1995), 1370-1378; Riedel, W. and Jolles, J.. Drugs & Aging, 8, (1996), 245-274).
  • the neuropeptide substance P prevents ⁇ -amyloid-induced neuronal loss and expression of Alz-50 proteins in cerebral cortex (Kowall, N., Beal, M.F., Busciglio, J., and Duffy, L.K.: Proc. Natl. Acad. Sci., 88, (1991), 7247-7251).
  • cerebral ACh content decreased, and the cerebral function suffers from severe damage (O'Leary, R. and O'Connor, B.: J. Neurochem., 65, (1995), 953-963).
  • a PEP inhibitor by increasing the level of TRH, could induce ACh release in the brain which should result in a better cognitive performance. It can be supposed that a highly specific PEP inhibitor could prove to be useful in the treatment of diseases of the central nervous system in neurodegenerative illnesses.
  • EP 0 419 683 A1 discloses prolylendopeptidase inhibitors on the basis of amino acid derivatives which comprise carbonyl-prolyl (or thioprolyl)-pyrrolidine (or thiazolidine) and groups coupled, eventually through alkylene and/or oxy or NH groups, to a 2-oxo-1-pyrrolidinyl or a phenylalkyl group.
  • Suitable PEP inhibitors as new drugs should be a
  • Senile dementia and Alzheimer's disease become serious and fastly outgrowing problem of the aging population and a PEP inhibitor could be useful for the general treatment of the above mentioned serious diseases.
  • the new PEP-inhibitors of the present invention display advantageous characteristics and may serve as active ingredients of new drugs.
  • the advantages are a strong PEP-inhibitory effect, selectivity, easy transfer through the blood-brain barrier, a long half-life, good oral resorption, enhanced chemical and biological stability and an advantageous therapeutical profile including lower toxicity and low probability of side effects.
  • the compounds of the present invention are of the general formula (I), wherein are:
  • Preferred compounds of the present invention are compounds of formula (I) wherein are:
  • the compound of formula (I) is liberated from a salt thereof.
  • compositions of the present invention comprise one or more of the compounds of formula (I) together with usual carriers and/or auxiliary materials.
  • the present invention further pertains to the use of the compounds of formula (I) as defined above for preparing pharmaceutical compositions for the inhibition of the prolylendopeptidase (PEP) enzyme in mammals including man.
  • PEP prolylendopeptidase
  • alkyl group containing 1 to 6 carbon atoms means a straight chain or branched alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, neopentyl and hexyl.
  • aryl group of 6 to 10 carbon atoms means for example phenyl, tolyl or naphthyl groups.
  • Aralkyl groups of 6 to 10 carbon atoms are for example benzyl, 1-phenylethyl, 2-phenylethyl and 1-phenylpropyl.
  • Alkenyl group containing 1 to 6 carbon atoms means a straight chain or branched alkenyl group such as vinyl, allyl, methacryl, crotyl, 3-butenyl, 2-pentenyl, 4-pentenyl, 2-hexenyl or 5-hexenyl.
  • Alkinyl containing 1 to 6 carbon atoms means a straight-chain or branched alkinyl group such as ethinyl, propargyl, 2-butinyl, 3-butinyl, 2-pentinyl, 4-pentinyl, 2-hexinyl, 5-hexinyl or 4-methyl-2-hexinyl.
  • cycloalkyl part of an "acyl group containing 1 to 12 carbon atoms” means for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl. These definitions may be used in case of alkoxy, alkenyloxy, alkinyloxy, aryloxy, aralkyloxy, phenylalkyloxy or alkylamino or acylamino groups.
  • the supernatant was thawn just before activity measurement and diluted in a 1:15 ratio with PEP buffer.
  • the enzyme activity was measured by using the fluorometric method described by J.R. Atack et al. (Eur. J. Pharmacol., 205, (1991), 157-163).
  • the enzyme reaction was performed at room temperature for 15 min in the presence of 62.5 ⁇ M Z-glycyl-prolyl-7-amino-4-methyl-coumarin (Bachem Biochem.) as a highly specific synthetic substrate of the PEP.
  • the inhibitory effect of compounds was tested under the same conditions in the presence of 100 to 0.001 nM of the respective compounds.
  • the formation of 7-amino-4-methyl-courmarin was detected spectrofluorometrically at 370 nm excitation and 440 nm emission wavelength.
  • the 50 % inhibition concentration of the compounds (IC 50 ) was calculated by curve fitting of the % inhibition of the enzyme versus inhibitor concentration (M) using the Hill equation.
  • the IC 50 values of the compounds of the general formula (I) are in the range of 100 nM to 1 pM.
  • pig brain prolyl endopeptidase was a kind gift from Lásló Polgár of the Enzymology Institute of the Hungarian Academy of Sciences.
  • the enzyme solution was diluted in the reaction mixture 400000 times. Measurements were performed under the same conditions as in the case of the in vitro measurements on rat brain preparation.
  • the compounds of the general formula (I) were shown to be also active on pig brain PEP activity.
  • the new inhibitors of the general formula (I) were tested under the following conditions:
  • the reaction was terminated by addition of acetonitrile.
  • the samples were centrifuged at 3000 rpm for 10 min.
  • the supernatant was analyzed by HPLC (Supelcosil C18). The unchanged substrate amount was determined, and the half-lifes of the compounds were calculated.
  • Some compounds of the general formula (I) had a half-life on human liver microsomes of more than 7 h. Such a good biological stability favours a long lasting effect in vivo and is an advantage over other peptidic-type PEP-inhibitors which are known to be biologically unstable.
  • EP 0 232 849 A2 describes numerous PEP-inhibitors including SUAM-1221 (N-[N-( ⁇ -phenyl)-butyryl-L-prolyl]-pyrrolidine).
  • the compounds of the general formula (I) exert a high inhibition activity on prolyl endopeptidase which is greater than that of above reference compound SUAM-1221 measured in our above-described test system.
  • Table 1 shows a typical example.
  • Compound IC 50 (M) rat brain extract Example 23 3.60 ⁇ 10 -10 SUAM-1221 3.12 ⁇ 10 -8 .
  • the phthalimido group and the B units of the compounds of the general formula (I) are coupled by reaction of the appropriate acid anhydride or other activated acid derivative and an amine, yielding compounds of the general formula (II) as described above.
  • the coupling of the units C and L to yield compounds of the general formula (III) is carried out by reacting the appropriate mixed anhydride and the amine or an ester and a metallo-organic compound, respectively.
  • the starting compounds corresponding to the phthalimido unit and the units B, C and L are commercially available or easy to obtain by known transformation of them or as described in Chem. Pharm. Bulletin 41 (9) (1993), p. 1583-1588.
  • the coupling reaction can favourably be carried out in an organic solvent, preferably at a temperature between -25 °C and the boiling point of the reaction mixture.
  • acid binding agents e.g. organic amines
  • the compounds of the general formula (I) can be purified, if appropriate, by a conventional purification technique, the isomers of which are separated, if desired, by a conventional separation technique and which are converted, if necessary, to their addition salts with a pharmaceutically acceptable acid.
  • Pharmaceutically acceptable acids may be for example hydrochloric, sulfuric, tartaric, fumaric or methanesulfonic acid and the like.
  • compositions containing, as active ingredient, at least one compound of the general formula (I) or one of its addition salts with a pharmacologically acceptable acid, alone or in combination with one or more inert and non-toxic excipients or vehicles.
  • compositions according to the invention Mention may more particularly be made, among pharmaceutical compositions according to the invention, of those which are suitable for oral, parenteral, rectal or nasal administration, and which may be simple or sugar-coated tablets, sublingual tablets, injectable compositions, infusions, packets, gelatine capsules, suppositories, creams, ointments, dermal gels, and the like.
  • the dose varies according to the age and weight of the patient, the nature and the severity of the ailment and the administration route.
  • the latter can be oral, nasal, rectal or parenteral.
  • the unit dose generally varies between 0.1 and 50 mg/kg body weight for a treatment taken with 1 to 3 administrations per 24 h.

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Claims (11)

  1. Verbindungen der allgemeinen Formel (I),
    Figure 00290001
    worin bedeuten:
    R1, R2, R3 und R4 unabhängig
    Wasserstoff,
    Halogen,
    Hydroxy,
    Cyano,
    Nitro,
    Amino,
    Anilino,
    Mercapto,
    Carboxy,
    Phenyl,
    Phenoxy,
    Benzyl,
    Benzyloxy,
    Benzoyl,
    Cyanato,
    Isocyanato,
    Thiocyanato,
    Isothiocyanato,
    Sulfamino,
    Sulfamoyl,
    Alkylthio mit 1 bis 6 Kohlenstoffatomen,
    geradkettiges oder verzweigtes Alkyl, Alkenyl, Alkinyl, Alkoxy, Alkenyloxy oder Alkinyloxy mit 1 bis 6 Kohlenstoffatomen,
    Monoalkylamino oder Monoacylamino mit 1 bis 12 Kohlenstoffatomen,
    Dialkylamino oder Diacylamino mit 2 bis 24 Kohlenstoffatomen, wobei die Acylgruppe vom Alkyl-, Aralkyl-, Cycloalkyl- oder Aryltyp ist,
    verestertes Carboxy mit 2 bis 7 Kohlenstoffatomen,
    Hydroxyalkyl mit 1 bis 6 Kohlenstoffatomen,
    Acyl mit 1 bis 7 Kohlenstoffatomen
    oder
    Acyloxy mit 1 bis 7 Kohlenstoffatomen;
    B eine Gruppe der Formel
    Figure 00300001
    in der R9, R10, R11, R12, R13 und R14 unabhängig bedeuten:
    Wasserstoff,
    Phenyl,
    mit 1, 2 oder 3 Halogenatomen substituiertes Phenyl oder
    Alkyl mit 1 bis 6 Kohlenstoffatomen,
    wobei
    w gleich 0 oder 1 ist;
    C
    Prolyl,
    Figure 00310001
    Figure 00310002
    oder
    Figure 00320001
       wobei Hal F, Cl, Br oder I bedeutet,
    •
    Figure 00320002
       oder
    •
    Figure 00320003
    wobei n 0, 1 oder 2 bedeutet,
    •
    Figure 00330001
    wobei die gestrichelten Linien gegebenenfalls vorliegende chemische Bindungen bedeuten,
    und
    L
    Pyrrolidino,
    2-Cyanopyrrolidino,
    Thiazolidino oder
    2-Cyanothiazolidino,
    die gegebenenfalls mit einem Halogenatom oder geminal mit zwei Halogenatomen substituiert sind,
    Figure 00330002
       wobei R17 Wasserstoff oder Cyano und
       n 0, 1 oder 2 bedeuten,
    Figure 00340001
    und die Salze der Verbindungen der Formel (I),
    wobei die optischen Isomeren, die cis-trans-Isomeren, die geometrischen Isomeren, die Epimeren und die Tautomeren eingeschlossen sind.
  2. Verbindungen der Formel (I) nach Anspruch 1, worin bedeuten:
    B -(CH2)m-CO-,
       wobei m 2 oder 3 bedeutet,
    C
    Prolyl,
    Figure 00340002
    oder
    Figure 00350001
       wobei n 1 oder 2 bedeutet,
    und
    L
    Pyrrolidino
    oder
    Thiazolidino,
    sowie die Salze dieser Verbindungen der Formel (I),
    wobei die optischen Isomeren, die cis-trans-Isomeren, die geometrischen Isomeren, die Epimeren und die Tautomeren eingeschlossen sind.
  3. Verfahren zur Herstellung von Verbindungen der allgemeinen Formel (I) wie in Anspruch 1 oder 2 definiert,
    gekennzeichnet durch
    Umwandlung einer Verbindung der Formel (II),
    Figure 00360001
    in der R1 bis R4 und B wie in Anspruch 1 oder 2 definiert sind,
    in ein Säurehalogenid, einen aktiven Ester, ein gemischtes Säureanhydrid oder ein Carbodiimid
    und
    Umsetzung der resultierenden Verbindung mit einer racemischen oder optisch aktiven Verbindung der Formel (III), H-C-L worin C und L wie in Anspruch 1 oder 2 definiert sind,
    oder einem Salz davon,
    und wahlweise Auftrennung der resultierenden Verbindung der Formel (I) in ihre optischen Isomeren, cis-trans-Isomeren, geometrischen Isomeren, Epimeren oder Tautomeren.
  4. Verfahren zur Herstellung von Verbindungen der allgemeinen Formel (I) wie in Anspruch 1 oder 2 definiert, gekennzeichnet durch Freisetzung der Verbindung der Formel (I) aus einem ihrer Salze.
  5. Verfahren nach Anspruch 3, dadurch gekennzeichnet, dass ein Säureadditionssalz der Verbindung der Formel (III) eingesetzt wird.
  6. Verfahren nach Anspruch 3 oder 5, dadurch gekennzeichnet, dass ein reaktives gemischtes Anhydrid einer Verbindung der Formel (II) unter Verwendung von Pivaloylchlorid hergestellt wird.
  7. Verfahren nach einem oder mehreren der Ansprüche 3, 5 oder 6, dadurch gekennzeichnet, dass die Umsetzung in einem organischen Lösungsmittel durchgeführt wird.
  8. Verfahren nach einem oder mehreren der Ansprüche 3, 5, 6 oder 7, dadurch gekennzeichnet, dass die Umsetzung bei einer Temperatur zwischen -25 °C und dem Siedepunkt des Reaktionsgemisches durchgeführt wird.
  9. Verfahren nach einem oder mehreren der Ansprüche 3, 5, 6, 7 oder 8, dadurch gekennzeichnet, dass die Umsetzung in Gegenwart eines säurebindenden Mittels durchgeführt wird.
  10. Pharmazeutische Zusammensetzungen, die eine oder mehrere Verbindungen der Formel (I) nach Anspruch 1 oder 2 zusammen mit üblichen Trägern und/oder Hilfsstoffen enthalten.
  11. Verwendung der Verbindungen der Formel (I) wie in Anspruch 1 oder 2 definiert zur Herstellung von pharmazeutischen Zusammensetzungen zur Inhibierung des Enzyms Prolylendopeptidase (PEP) bei Säugern einschließlich des Menschen.
EP96925926A 1995-08-17 1996-07-26 Prolylendopeptidase-inhibitoren, ihre herstellung und ihre pharmazeutische verwendung Expired - Lifetime EP0861246B1 (de)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
HU9502426 1995-08-17
HU9502426A HUT76640A (en) 1995-08-17 1995-08-17 Compounds of pharmaceutical activity cyclic amide derivatives, pharmaceutical compositions containing them, process for producing them and their use
PCT/HU1996/000041 WO1997007116A1 (en) 1995-08-17 1996-07-26 Prolylendopeptidase inhibitors

Publications (2)

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EP0861246A1 EP0861246A1 (de) 1998-09-02
EP0861246B1 true EP0861246B1 (de) 2003-10-15

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EP (1) EP0861246B1 (de)
JP (1) JPH11514970A (de)
KR (1) KR19990037669A (de)
CN (1) CN1092193C (de)
AR (1) AR009225A1 (de)
AT (1) ATE252096T1 (de)
AU (1) AU725429B2 (de)
BG (1) BG102323A (de)
BR (1) BR9610075A (de)
CA (1) CA2235677A1 (de)
CZ (1) CZ45798A3 (de)
DE (1) DE69630391T2 (de)
EA (1) EA001399B1 (de)
EE (1) EE9800044A (de)
HR (1) HRP960375B1 (de)
HU (1) HUT76640A (de)
IL (1) IL123268A0 (de)
IS (1) IS4668A (de)
MX (1) MX9801190A (de)
NO (1) NO980643L (de)
NZ (1) NZ313751A (de)
PL (1) PL325013A1 (de)
SK (1) SK18998A3 (de)
TR (1) TR199800243T1 (de)
TW (1) TW486476B (de)
WO (1) WO1997007116A1 (de)
YU (1) YU47096A (de)
ZA (1) ZA966554B (de)

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HUP9700442A1 (hu) * 1997-02-14 1999-09-28 Chinoin Gyógyszer és Vegyészeti Termékek Gyára Rt. Gyűrűs amidszármazékok, e vegyületeket tartalmazó gyógyászati készítmények, eljárás előállításukra és alkalmazásuk
HUP0101470A3 (en) 1998-03-31 2002-09-30 Warner Lambert Co Quinoxalinones as serine protease inhibitors such as factor xa and thrombin and medicaments containing the compounds
IL136605A0 (en) 1998-03-31 2001-06-14 Warner Lambert Co Quinolones as serine protease inhibitors
US8642051B2 (en) 2000-03-21 2014-02-04 Suzanne Jaffe Stillman Method of hydration; infusion packet system(s), support member(s), delivery system(s), and method(s); with business model(s) and Method(s)
CA2536313A1 (en) * 2003-08-22 2005-03-03 Takeda Pharmaceutical Company Limited Fused pyrimidine derivative and use thereof
US7320992B2 (en) * 2003-08-25 2008-01-22 Amgen Inc. Substituted 2,3-dihydro-1h-isoindol-1-one derivatives and methods of use
WO2005030217A1 (en) * 2003-09-23 2005-04-07 Merck & Co., Inc. Quinazoline potassium channel inhibitors
WO2006058720A2 (en) 2003-11-03 2006-06-08 Probiodrug Ag Novel compounds for the treatment of neurological disorders
ZA200708179B (en) * 2005-04-22 2009-12-30 Alantos Pharmaceuticals Holding Inc Dipeptidyl peptidase-IV inhibitors
EP2730571A1 (de) * 2012-11-12 2014-05-14 Universitat De Barcelona 1-[1-(Benzoyl)-pyrrolidin-2-carbonyl]-pyrrolidin-2-carbonitril-Derivate
US9392814B2 (en) 2014-06-06 2016-07-19 Nicholas J. Singer Delivery system for drinks
USD773313S1 (en) 2015-06-23 2016-12-06 Nicholas J. Singer Package
JOP20170113B1 (ar) * 2016-05-09 2023-03-28 Bayer Pharma AG مركبات 5، 6، 7، 8-رباعي هيدرو [1، 2، 4] تريازولو [4، 3-أ] بيريدين 3(2h)-ون مستبدلة ومركبات 2، 5، 6، 7-رباعي هيدرو-3h-بيرولو [2، 1-ج] [1، 2، 4] تريازول-3-ون واستخداماتها

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CA1320734C (en) 1986-02-04 1993-07-27 Suntory Limited Pyrrolidineamide derivative of acylamino acid and pharmaceutical composition containing the same
CA2004028C (en) * 1988-12-08 1998-09-22 Motoki Torizuka Condensed benzene derivative
US5118811A (en) * 1989-04-13 1992-06-02 Japan Tobacco Inc. Amino acid derivatives possessing prolyl endopeptidase-inhibitory activities
EP0468469A2 (de) * 1990-07-27 1992-01-29 Japan Tobacco Inc. Prolinderivate

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KR19990037669A (ko) 1999-05-25
US6191161B1 (en) 2001-02-20
NO980643D0 (no) 1998-02-16
DE69630391T2 (de) 2004-06-24
HU9502426D0 (en) 1995-10-30
AU725429B2 (en) 2000-10-12
NO980643L (no) 1998-04-07
HRP960375A2 (en) 1998-02-28
PL325013A1 (en) 1998-07-06
AU6627996A (en) 1997-03-12
YU47096A (sh) 1998-12-23
TW486476B (en) 2002-05-11
DE69630391D1 (de) 2003-11-20
CN1092193C (zh) 2002-10-09
SK18998A3 (en) 1998-07-08
EE9800044A (et) 1998-08-17
BG102323A (bg) 1998-12-30
ATE252096T1 (de) 2003-11-15
EA001399B1 (ru) 2001-02-26
JPH11514970A (ja) 1999-12-21
EA199800200A1 (ru) 1998-10-29
ZA966554B (en) 1997-02-24
MX9801190A (es) 1998-04-30
CN1196728A (zh) 1998-10-21
IL123268A0 (en) 1998-09-24
HRP960375B1 (en) 2003-06-30
AR009225A1 (es) 2000-04-12
CZ45798A3 (cs) 1998-07-15
WO1997007116A1 (en) 1997-02-27
EP0861246A1 (de) 1998-09-02
HUT76640A (en) 1997-10-28
BR9610075A (pt) 1999-03-02
IS4668A (is) 1998-02-16
TR199800243T1 (xx) 1998-06-22
CA2235677A1 (en) 1997-02-27
NZ313751A (en) 2000-01-28

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